1-aroylbenzimidazoles

ABSTRACT

1-AROYLBENZIMIDAZOLES AND 1-AROYLBENZOTRIAZOLES AND THEIR USE AS ANTI-INFLAMMATORY AGENTS IN THE TREATMENT OF ARTHRITIC DISORDERS.

United States Patent [72] Inventor Reinhard Surges Mystic, Conn. [21]Appl. No. 714,416 [22] Filed Mar. 20, 1968 [45] Patented Dec. 7, 1971[73] Assignee Pfizer Inc.

[54] l-AROYLBENZIMIDAZOLES 2 Claims, No Drawings [52] US. Cl 260/309.2,

260/295 AM, 260/308 B, 260/473 A, 260/473 R,

260/474, 424/269, 424/273 [51] Int. Cl C07d 49/38 [50] Field of Search260/309.2

[56] References Cited UNITED STATES PATENTS 3,055,907 9/1962 Brown et al260/3092 3,325,506 6/1967 Jones et a1. 260/302 1-1 3,336,192 8/1967Sarett et a1 260/302 H 3,429,890 2/1969 Sletzinger et a1 260/302 H3,471,508 10/1969 Sarett et al 260/302 H FOREIGN PATENTS 1,503,58010/1967 France 1,151,424 5/1969 GreatBritain OTHER REFERENCES Bishop etaL, J. Chem. Soc. (London) 1964, pp. 3076- 80. QDl.C6

Dornow et al., Angew. Chem., Vol. 66, pg. 605 (1954) QD1.25

Morgan et al., J. Chem. Soc. (London) 1961, pp. 2346- 2347 relied onQD1.C6, 260- 302H Netherlands Application 6412728, May 1965, pp. 1- 5relied on, 260- 3021! Netherlands Application 6413474, May 1965, pp. l-4 relied on, QD 1 .D4

Staab et a1., Chem. Ber, V01. 99, pg. 2961 relied on 1966) PrimaryExaminer Natalie Trousof A!!orneyConn0l1y and Hutz ABSTRACT:l-aroylbenzimidazoles and l-aroylbenzotriazoles and their use asanti-inflammatory agents in the treatment of arthritic disorders.

l-AROYLBENZIMIDAZOLES -N BACKGROUND OF THE INVENTION I This inventionrelates to a series of novel l-aroyl- R1 benzimidazoles andl-aroylbenzotriazoles having valuable therapeutic properties. Inparticular, this invention is concerned with the preparation of novell-aroylbenzimidazoles and l-aroylbenzotriazoles possessinganti-inflammatory activity in mammals. Ra

Although l-benzoylbenzimidazole, l-benzoylbenzotriazole and a limitednumber of other substituted l-aroyl benzimidazoles and benzotriazolesare known, the compounds wherein euher zpyndyl or CF11 and R8 e'ther ofthe present invention have now been prepared for the first 0r OCH2CO2Htime. The l-aroylbenzotriazoles included within the Instant inven- Thediscovery and preparation of therapeutic agents effec 15 tion includethose having the structural formulas:

tive in alleviating arthritic disorders presents a formidable challenge,particularly in view of the fact that its etiology and --N pathogenesisare not presently fully understood, although R various theoriesregarding the cause of the disease have been advanced. Human arthriticdisorders, particularly rheumatoid N arthritis, are evidenced byswelling, pain, tenderness, and inflammation of the joints. During theearly stages of the dis- 1 ease, the joints usually appear red andcontain considerable Rm amounts of fluid.

Various anti-inflammatory agents, e.g.,the salicylates, have wherein iseither Cl ohBrj and Rm may be p y been found to alleviate the subacuatesymptoms of the dfmethylamlhophehyli 3i4is'h'lmethoxyphehyl andarthritis and have been widely used therapeutically to treatdlmethoxyphehyl- Subjects afflicted i the disease We have surprisinglydiscovered that many of the novel Many of the compounds described in theinstant invention 0 Compounds descfibed f 'h h contrast to lfhowhinhibit artificially induced edema formation in rats, a property P ofthe Senesi exhlhh a hlgh degree of ahh'lhflammalowhich is considered bythoseskilled in the art as being indicay a t in mammals, and areeffective preventing and tive of a compounds potential usefulness as ananti-inflammahlbmhg the formahoh of grahulolhatous hssue- Consequently,

tory agent in the treatment f arthritic disorders. these compounds areof value in the treatment of those arthritic disorders which areresponsive to treatment with anti- SUMMARY OF THE INVENTION inflammatoryagents.

This invention comprises the preparation of novel l-aroyl- DETAILEDDESCRIPTION OF THE INVENTION benzimidazoles and l-aroylbenzotriazoleshaving anti-inflammatory activity. Among the novel l-aroylbenzimidazolesThe ljaroylhehllmldazoles f y of described herein are those having thefollowing structural for- 40 l 'hvehhoh are cohvehlehtly P p y Teachhgthe l appropriate benzimidazole or benzotriazole with an aroyl halide,preferably the chloride, in an alert anhydrous solvent in the presenceof an organic base. Among the many solvents that may be employed arebenzene, dialkyl ethers, and

J tetrahydrofuran. We have found tetrahydrofuran to be a con- R2 venientsolvent with these reactions. The preferred organic I bases include thetrialkylamines such as triethylamine. Where C=O the benzimidazole orbenzotriazole contains a carboxy group I in the phenyl portion of themolecule, it is preferred to use up to 2 moles of organic base for everymole of aroyl halide used;

It although it should be understood that this aspect of the reaction isnot critical. In those situations where it is desired to 7 prepare al-aroylbenzimidazole containing a carboxyl function, e.g., -CO H and OCHCO H, in the aroyl portion of the compound, the preferred syntheticscheme is to aroylate wherein can be CH3 CO2", Cl and Br; e can be thebenzimidazole with an aroyl halide: containing the benzyl NHCOCFQ, andCH2CH2CO2H and can be either H, CL ester of the desired carboxyfunctionality and then remove the or Br; benzyl group of the resultantcompound by hydrogenolysis to provide the desired compound. Thus, forexample, the procedure in chart I has been used in R N preparing al-aroylbenzimidazole containing a OCH CO H J functionality in thel-aroyl moiety.

CHART I I Preparation of intermediates 0 0,11 6 o t-butyl Be isobutyleneBrCH C 02011205115 OH OH H+ NaH C O; t-butyl R can be either CH or --OCHR may be either H or F50 1 CH and R can be --CO H, -N(CH OCH CO H, orOLUICOQCHCMB "m OCH- CO CH C H5. provided that R, is CH 0- when R is H;A

A hydroxybenzoic acid is converted to the corresponding tbutyl ester byreaction with isobutylene in the presence of a mineral acid. The esteris then reacted with a benzyl haloacetate in the presence of sodium orpotassium hydride to give the diester A (see chart I), which is usuallynot isolated and purified, but is converted with trifluoroacetic acid tothe substituted benzoic acid H, shown in chart I latter compound isconverted to the corresponding acid halide C, which is used tobenzoylate the benzimidazoles and benzotriazoles. If desired, the benzylgroup in the ester moiety of the resultant compounds can be easilyremoved by hydrogenolysis to the corresponding acid functionality, i.e.,-OCH CO H.

A similar procedure is followed where it is desired to prepare acarboxy-containing l-aroyl moiety. Thus, the monoester of a phthalicacid is converted to the corresponding acid chloride, which is then usedfor aroylation. Here again;

after the l-aroylbenzimidazole is prepared, the carbobenzoxy group iseasily transformed into the corresponding carboxy group byhydrogenolysis.

Similarly, we prefer to prepare the1-aroyl-2-(2-carboxyethyl)benzimidazoles by first aroylating the benzylester of the 2-(2-carboxyethyl)benzimidazole and then converting thebenzyl ester moiety of the resultant compound to the carboxyfunctionality by hydrogenolysis.

Cl N

Cl N

5 N3 5 N3 l i 6 \Nl 6 NI/ 1 7 H w H Table A contains resultsillustrating the anti-inflammatory activity of a number of the compoundsof the present invention, as determined by the inhibition of edemaformation in the hind paw of rats (Charles River Strain; average weightg.) in response to a subplantar injection of carrageenin (ratfoot edematest"). The experimental procedures followed are those of Winter et al.as reported in Proc. Soc. Exp. Biol., N.Y., l 1 l, 544 (1962) AND J.Pharmacol. Exp. Therap., l4l, 369 (1963).

In this test, unanesthetized adult male albino rats of 150 g. to g. bodyweight are numbered, weighed, and an ink mark placed on the rightlateral malleolus. Each paw is immersed in mercury exactly to the inkmark. The mercury is contained in a glass cylinder, connected to aStatham Pressure Transducer. The output from the transducer is fedthrough a control unit to a microvoltameter. The volume of mercurydisplaced by the immersed paw is read. Drugs are given by gavage. Onehour after drug administration, edema is induced by injection of 0.05ml. of 1 percent solution of carrageenin into the plantar tissue of themarked paws. lmmediately thereafter, the volume of the injected foot ismeasured. The increase in foot volume 3 hours after the injection ofcarrageenin constitutes the individual response. The increase in volumeof the feet of the drug-treated animals are compared with those justreceiving vehicle alone.

On the same day that the compound under investigation is being tested,the above test procedure is also conducted with a second group ofanimals using acetylsalicylic acid (aspirin) instead, and theeffectiveness of each compound then expressed relative to aspirin.

TABLE A.-ANTIINFLAMMATORY ACTIVITY OF COM- POUNDS OF THE PRESENTINVENTION Rat foot edema test Inhibition ol Inhiedema, bitlou Dosage,per- Compound mgJkg. cent edema 1 1-(3,4,5-trimethoxybenzoyl)-benzlmidazol 100 .24. 8 0. 4S 1-(4-dlmethylamlnobenzoyl)4,6-

dlrnethylbenzlmldazole 100 48. 0 0. 78 D0 33 14. T 0.331-[4-(a-benzyloxyearbonyl)-meth0x 100 33. 3 0. 69benzoyl]6,6-dlmethylbenzimidazole 33 27. 4 0. 571-(4'-a-earboxymethoxybenzoyl)-5.-6

dimethylbenzimidazole. 100 14. 5 0. 3O 1-(4-carb0Xybenzoyl)-6,6d

benzimtdaz e 100 26. 3 0. 36 1-(4-ehlorobenzoyl)- benzlmldazole 100 24.4 0.38 1-(4'-acarboxymethoxybenzoyl)-2- 100 31. 9 0, 55

trifiuoromethylbenzimidazole 33 28. 31-benzoyl-2-trifiuoromethyl-5-methylbenzimidazole 100 42. 2 0. 59l-benzoyI-Z-trifluoromethyl-fi-chloro benztmidezole 100 55. 2 0.861-benzoyl-2-trifluoroacetamido-5- chlorobenzimidazole 100 30. 4 0. 6t1-(4-ch1orobenzoyl)-2-trifluoroaeetamidochlorobenzimidazole 100 16. 10.31 1-benzoyl-2-(2'-earboxyethyl)-5- chlorobenzimidazole 100 13. 2 0. 31-benzoyl-2-methy1-5,6-d1rnethoxybenzimidazole 100 30. 0 0. 641-benzoyl-2(2-pyridyl)-benz1midazole- 100 22. 4 0. 321-(1-naphthoybbenzimidazole 100 18. 7 0. 31 H4-(a-benzyloxycarbonyl)-methoxybenzoyl]6,6-dimethylbenzotriazole 100 1!).4 O. 40 1-(4-dlrnethylaminobenzoyl)-5- chlorobenzotrlazole 100 19. 4 0.2H 1-benzoyl5-chlorobenzotriazolu 100 44. 0 0. 021-(3-4-5-trimethoxybenzoyl)l5- chlorobenzotrlazole 100 28. 2 0.40 41(26dlmeth0xybenzoyl) -5-chlorobenzotrlazole 100 17. 0

1 Relative cfiectlveness compared to aspirin.

While many of the novel compounds described herein exhibit significantanti-inflammatory activity, some of the novel compounds prepared show noactivity. ln table B are listed representative examples of novelcompounds which were prepared, but which exhibited no pronouncedactivity in the R.F.E. screen.

TABLE B Rat foot edema test Inhibltlon of Inhiedema, bitlon Dosage, per-01 Compound mgJkg. cent edema 1-benz0yl-5,6-dimethylbenzimidazole 1007.6 0.13

1-(3,4,5-trimethoxybenz0yl)-5,6-

dimethylbenzimidazole 1-(4methoxybenz0ly)-2-methyl-5,6-

dlmethoxybenzimidazole 1-(Q-chl0robenz0yl-5-chlorobenzoyltriazole1-(4'dimethylaimnobenz0yl-5,6dlmethyl benzotriazole- 1 Relativeeffectiveness compared to aspirin.

A number of l-aroyl benzimidazoles and benzotriazoles previouslydescribed in the prior art that we have tested do not show anypronounced activity, with but one exception, as can be seen by examiningtable C.

TABLE C.ANTIINFLAMMATORY ACTIVITY OF SOME 1 Relative efieetivenesscompared to aspirin. 2 Exhibits hyperglycemic activity in rats.

Indeed, l-benzoylbenzimidazole, the known parent compound of thel-aroyl-benzimidazoles described herein, as well as several other knowncompounds in the series, actually increases the edema formation!Further, several known l-acyl benzimidazoles and benzotriazoles failedto show any significant anti-inflammatory activity (see table B). Thus,in contrast to the known analogs, many of the novel compounds of theinstant invention show superior anti-inflammatory activity and areuseful in alleviating the swelling and inflammation exhibited byarthritic and rheumatic subjects.

These compounds can be administered either alone or in combination withpharmaceutically acceptable carriers. The proportion of activeingredient to carrier is determined by the solubility and chemicalnature of the compound, chosen route of administration and standardpharmaceutical practice. For oral administration in capsule form,preferred excipients are lactose and high molecular weight polyethyleneglycols. When aqueous suspensions are desired, the essential activeingredients are combined with emulsifying and/or suspending agents.Diluents such as ethanol, propylene glycol, glycerine and variouscombinations of diluents are employed. For parenteral administration,solutions of the active ingredients in combination with other solutessuch as glycose or saline are used. Such aqueous solutions should besuitably buffered, if necessary, to render them isotonic.

The dosage required to reduce inflammation and swelling in arthritic andrheumatic subjects will be determined by the nature and extent of thesymptoms and can be easily regulated by those skilled in the art.Generally, small dosages will be administered initially with a gradualincrease in dosage until the optimum level is determined. lt willgenerally be found that when the composition is administered orally,larger quantities of the active ingredient will be required to producethe same level as produced by a smaller quantity administeredparenterally. In general, from about 0.02 to 200 mg. of activeingredient per kilogram of body weight administered in single ormultiple dosage units effectively reduce inflammation and swelling inarthritic and rheumatic subjects.

Preparation of the Benziimidazoles Most of the l-unsubstitutedbenzimidazoles employed as precursors in the present invention have beendescribed in the prior art, e.g., 5,6-dimethylbenzimidazole,2-trifluoromethylbenzimidazole. The preparations of the remainingbenzimidazole precursors are described below.

2Tritluoroacetamido'5-chlorobenzimidazole This compound is prepared byreacting 2-amino-5- chlorobenzimidazole and trifluoroacetic anhydride inpyridine according to the procedure of NJ. Leonard, D. Y. Curtain and1(. M. Beck, .1. Am. Chem. Soc., 69, 2459 (1947). Yield 74 percent; m.p.3 l 5l6 C.

Anal. Calcd for C,,H .,ClF N ,O: 15.94.

C, 41.01; H, 1.91; N,

Z-Trifluoromethyl-S-carboxybenzimidazole Prepared from3,4-diaminobenzoic acid and trifluoroacetic acid according to theprocedure of M. A. Phillips, J. Chem. Soc., 2393 (1928). Yield 71percent; m.p. 278 C.

Anal. Calcd for C H F N O C, 46.96; H, 2.19; N, 12.17.

Found: 12.03 (0.47 percent ash).

C, 46.23; H, 2.28; N,

Preparation of Other l-Unsubstituted Benzimidazoles2-Trifluorobenzimidazoles containing methyl, halo, and carboxy groups invarious positions of the phenyl ring, e.g., 2-trifluoromethyl-S-methylbenzimidazole, can be conveniently prepared bythe methods of E. S. Lane, J. Chem. Soc., 534 (l955)and B. C. Bishop, A.S. Jones, and J. C. Tatlow, J. Chem. Soc., 3076 1964).

Benzotriazole lPrecursors The l-unsubstituted benzotriazoles used in thepresent invention have all been described in the prior art.

The following examples are provided to more fully illustrate the presentinvention, but are not to be construed as limiting the scope thereof inany way.

EXAMPLE I Into a ml., 3-necked flask, fitted with a mechanical stirrer,dropping funnel, and drying tube, is added 2.36 g. (0.02 moles) ofbenzimidazole dissolved in 50 ml. of anhydrous tetrahydrofuran.Triethylamine (2.02 g., 0.02 moles) is added and the mixture is cooledto 0 C.

While the mixture is stirred vigorously at 0 C., 3.81 g. (0.02 moles) ofl-naphthoyl chloride, dissolved in a small amount of tetrahydrofuran, isadded dropwise over a period of 15 minutes. The cooling bath is removed,and the reaction mixture is allowed to come to room temperature. Afterstirring the reaction mixture at room temperature for about 2 hours, thetriethylamine hydrochloride is filtered and washed with a small amountof tetrahydrofuran. The: filtrate is evaporated, and the crudel-naphthoylbenzimidazole is recrystallized from ethyl acetate-ligroin.Yield 28 percent; m.p. 108-1 10 C.

7 8 Anal. Calcd for C H N O: C, 79.39; H, 4.44; N, 10.29.l-(2'-bromobenzoyl)-2-trifluoromethyl-5- Found: C, 79.32; H, 4.62; N,chlorobenzimidazole 10.16. l-( 2'-chlorobenzoyl )-2-trifluoromethyl-5-chlorobenzimidazole EXAMPLE nl-benzoyl-2-trifluoromethyl-4-bromobenzimidazolc Employing theconditions and procedures of example I, 9 9 y 0.020 moles ofbenzimidazole is reacted with 0.020 moles of bromoPenzlmldazole3,4,5-trimethoxybenzoyl chloride. The yield of 1-3', 4', 5'- y ytrimethoxybenzoylbenzimidazole is 80 percent; m.p. l28-l2bromobenzlmldazolc 9C. 10 l-(3'-bromobenzoyl)-2-trifluoroacetamido-5-Anal. Calc'd for C,,H,,, N O C, 65.37; H, 5.16; N, 8.97. hl r nzimi z leFound: C, 65,45; H 5 15; N,l-benzoyl-2-trifluoroacetamido-4-bromobenzlmidazole 9.13.l(4'-chl0robenzoyl)-2-trifluoroacetamido- 4bromobenzimidazole EXAMPLEl-(3-chlorobenzoyl)-2-trifluoroacetamido-4- dazole Employing theconditions and procedures of example I, the bromobenzlm'l-benzoylbenzimidazoles tabulated in table l are prepared f W i i g z ih I from the appropriate benzoyl chlorides and l-unsubstitutedfd'methylammobenzoy 'mmet y benzimidazoles. benzlmldazole TABLE IElemental analysis Meltlng Calculated Found point, Yield,l-aroylbenzimidazole C. percent 0 H N C II Nl-4-dimethylamino-6.fi-dimethylbenzlmldazole. 205-207 41 73.60 6. 5314.33 73. 83 6.54 14.05 1-4-chlorobenzoyl-2-trlfiuoromethylbenzlmidazole110-120 56 55.50 2. 48 8.63 56.19 2. 56 6.671-benz0y1-2-2-pyridylbenzlmldazole 134-37 9 70.24 4. 38 14.04 76.11 4.1114.00 1-benzoyl-2-trifiouromethyl-5-methylbenzlmldazole 91-3 26 63.153.65 9.21 63.12 3. 68 9.291-benzoyl-2-trifluoromethy1-5-chlorobenzimidazole 65-8 39 55.50 2. 48 8.03 55. 53 2.42 8.71 l-benzoyl-Z-tnfluoromethyl-5-carboxybenzimidazole167-69 65 57.48 2.70 8. 38 57.33 2.96 8.271-4'-ch1orobenzoyl-Z-trifiuoromethyl-B-carboxybenzimidazole 157-60 6152.14 2.19 7.59 51.96 2.18 7.691-benzoyl-2-trlt1uoroacetamldo-Hhlorobenzimldazole 228- 46 52.27 2. 4611.43 51.97 2.80 11. 201-4-chlorobenzoyl-Z-trifiuoroaeetamido-5-chlorobenzimidazole 233-5 4047.78 2.01 10. 47. 93 2.09 10. 39l-benzoyl-2-methy1-5,6-dimethoxybenzlmidazole. 136-37 85 68.90 5. 44 0.45 68.68 5.56 9. 58 1-benzoyl-5,6-dimcthylbenzlmidazole 28-29 75 76. 785. 64 11.19 76.05 5.50 11.381-(3,4',5-trimethoxybenzoyl)-5,6-dimethylbenzimidazole 155-57 94 67. 045.92 8.23 66.93 5.89 8.291-(4-methoxybenzoyl)-2-methyl-5,6-dlmethoxybenzimidazole 145-46 60 66.245.56 8.58 66.15 5.65 8.90

EXAMPLE lV l-benzoyl-S ,6-dimethoxybenzimidazole 45l-(4'-dimethylaminobenzoyl)-5,6-dimethoxybenzimidazole Employing theconditions and procedures of example I, the l (4, dimethylaminobenzoyl)2 methy1 56 dimethoX l-aroyl benzlmldazoles listed below are readilyprepared from ybenzimidazole the appropriate l-unsubstitutedbenzimidazoles and benzoyl 1 (4l chlombenzoyl) 2 (2, pyridyl)benzimidazole chlond'es' l-( 2'-bromobenzoyl )-2-( 2'-pyridyl)-benzimidazolejchlombemylHm"urmethyl-5'methyll-(3-bromobenzoyl)-2-trifluoromethylbenzimidazolebenzimidazole l-( 3 -chlorobenzoyl)-2-tr|fluoromethyl-S-methyl- EXAMPLEv benzimldazole l-(4'-chlorobenzoyl)-2-trifluoromethyl-5-methyl- A.Preparation of t-butyl-p-hydroxybenzoate benzimidazole One mole (138 g.)of p-hydroxybenzoic acid is dissolved inl-(2'-bromobenzoyl)-2-trifluoromethyl-5-methyl- 1 liter of methylisopropyl ketone. After adding l0 ml. of a benzimidazole concentratedsulfuric acid, the solution is saturated at 0 C.

l-(4'-bromobenzoyl)-2-trifluoromethyl-5-methylwith isobutylene. Themixture is allowed to stand at room tembenzimidazole perature for 2 daysand is then diluted with 400 ml. of etherl-benzoyl-2-trifluoromethyl-4-methylbenzimidazole l-(4- and washedsuccessively with 5 percent sodium bicarbonatechlorobenzoyl)-2-trifluoromethyl-4-methylbenzimidazole solution andwater. After drying the ether solution overanl-(3-bromobenzoyl)-2-trifluoromethyl-4-methylhydrous magnesiumsulfate, it is evaporated and the crude tbenzimidazolebutyl-p-hydroxybenzoate is recrystallized from ether-ligroin.

l-benzoyl-2-trifluoroacetamido-4-methylbenzimidazole Yield 78 g. (40percent); m.p. l30-l 32 C. l-(3'-chlorobenzoyl)-2-trifluoroacetamido-4-methyl- Anal. Calcd for C H OC, 68.02; H, 7.27. benzimidazole Found: C, 67.78; H, 7.28.

l-(4'bromobenzoyl)-2-trifluoroacetamido-4-methyl- Similarly, t-butyloand m-hydroxybenzoate are prepared benzimidazole from oandm-hydroxybenzoic acids, respectively.

l-( 3'-brom0benzoyl)-2-trifluoromethyl-S-carbox- B. Preparation ofBenzyl (4-carboxyphenoxy)acetate ybenzimidazolel-benzoyl-2-trifluoroacetamido-5-carboxybenzimidazole l-( 3'-chlorobenzoyl 2-trifluoroacetamido-5-carboxybenzimidazole l 2-bromobenzoyl )-2-trifluoroacetamido-5-carboxybenzimidazole To asolution of 3.9 g.(0.02 moles) of t-butyl-p-hydroxybenzoate contained in[5 ml. of anhydrous dimethylformamide is added, in small portions, l g.of a 50 percent suspension of sodium hydride in mineral oil. Theresultant mixture is stirred and heated to 50 C. When the evolution ofhydrogen ceases, 4.2 g. (0.020 moles) of benzyl bromoacetate is addeddropwise to the stirred reaction mixture over a period of 20 minutes.After stirring the resultant mixture at 50 C. for 3 hours, it is cooledand filtered. The filtrate is evaporated and the oily residue of crudebenzyl(4-carb-o-t-butoxyphenoxy)acetate is stirred with 20 ml. oftrifluoroacetic acid at room temperature for 1 hour.

The reaction mixture is concentrated under vacuum with a rotaryevaporator and the residue of benzyl (4-carboxyphenoxy)acetate isrecrystallized from ethyl acetate-ligroin. Yield 4.2 g. (74 percent);m.p. 132-134 C.

Anal. Calcd for C H O C, 67.12; H, 4.93.

Found: C, 67.17; H, 5.08.

Similarly, benzyl (2-carboxyphenoxy)acetate and benzyl(3-carboxyphenoxy)-acetate are prepared from t-butyl hydroxybenzoate andt-butyl-m-hydroxybenzoate, respectively.

C. Preparation of Benzyl y)acetate The benzyl (4-carboxyphenoxy)acetateprepared in B above is refluxed with thionyl chloride for about 1 /2hours. The excess thionyl chloride is removed under reduced pressurewith a rotary evaporator. Recrystallization from etherligroin gives asubstantially quantitative yield of benzyl (4-chlorocarbonylphenoxy)acetate; m.p. 9092 C.

Anal. Calcd for C H ClQ: C, 63.07; H, 4.30.

Found: C, 63.17; H, 4.42.

Likewise, benzyl (2-chlorocarbonylphenoxy)acetate and benzyl(3-chlorocarbonylphenoxy)acetate are prepared from benzyl(2-carboxyphenoxy)acetate and benzyl (3-carboxyphenoxy)acetate,respectively.

D. Preparation of 1-[4-(abenzyloxycarbonyl)methoxybenzoyl]-2-trifluoromethylbenzimidazole2-Trifiuoromethylbenzimidazole and benzyl(4-ch1orocarbonylphenoxy)acetate are reacted according to the generalprocedure described in example l.

The yield of 1-[4'-(a-benzyloxycarbonyl)methoxybenzoyl]-2-trifluoromethyl-benzimidazole is 52 percent; m.p. l l4l 15 C.

(4-chlorocarbonylphenox- Anal. Calcd for C H F N- O C, 63.41; H, 3.77;N, 6.17.

Found: C, 63.85; H, 3.96; N, 5.78.

with a rotary evaporator to provide a 90 percent yield of 1-(4'-a-carboxymethoxybenzoyl )-Z-trifluoromethylbenzimidazole; m.p. 162-164C.

Anal. Calc'd for C H F N O C, 56.05; H, 3.05; N, 7.70.

Found: C, 56.36; H, 3.40; N,

7.52. Similarly, l-( 2 '-a-carboxymethoxybenzolZtrifiuoromethylbenzimidazole l-( 3'-a-carboxyrnethoxybenzoyl)-Z-trifluoromethylbenzimidazole are preparedfrom l-[ 2 a-benzyloxycarbonyl )methoxybenzoyl -2-trifluoromethylbenzimidazole and 1-[3-(a-benzyloxycarbonyl)methoxybenzoyl]-2-trifluoromethylbenzimidazole, respectively.

EXAMPLE Vl Employing the conditions and procedures of examples V-D andVE the l-aroyl benzimidazoles in table 11, column B, are prepared byreacting the benzyl (chlorocarbonylphenoxy)acetates listed in table 11,column A, with appropriate l-unsubstituted benzimidazoles.

TABLE II A B Benzyl (chlorocarbonylphenoxy) acetate l-AroylhenzimidazolcBenzyl (4- methyl-5.6-dirnethoxybenzimidazole EXAMPLE Vll A. Preparationof l-[4'-(a-benzyloxycarb0nyl)methoxybenzoyl]-5,6-dimethylbenzimidazole5,6-Dimethylbenzimidazole is reacted with benzyl (4-chlorocarbonyl-phenoxy)acetate according to the general procedure ofexample I to provide1-[-4'-(a-benzyloxycarbonyl)methoxybenzoyl1-5,6-dimethylbenzimidazole in48 percent yield; m.p. 159 160" C.

Anal. Calcd for C H N O C, 72.45; H, 5.35; N, 6.76.

Found: C, 72.42; H, 5.30; N, 6.81.

Similarly, the following l-aroyl benzimidazoles can be prepared byreacting benzyl (4-chlorocarbonylphenoxy)acetate with the appropriatelunsubstituted benzimidazole. 1-[4 a-benzyloxycarbonyl)methoxybenzoly]-2,5 ,6 trimethylbenzimidazolel-[4'-(a-benzyloxycarbonyl)methoxybenzoylJ-S,6-dimethoxybenzimida2ole1-[4-(a-benzyloxycarbonyl)methoxybenzoyl]-2methyl-5,6-dimethoxybenzimidazole B. Preparation of l-(4'-a-carboxymethoxybenzoyl)-5,6-dimethylbenzimidazole Hydrogenolysis of1-[4'-(a-benzyloxycarbonyl)methoxybenzoyl1-5,-dimethylbenzimidazoleaccording to the procedure of example V-E provides 1-(4'-a-carboxymethoxybenzoyl)-5,6-dimethylbenzimidazole; m.p. l88190 C.

Anal. Calcd for C,,,H,,,N O.,: 10C, 66.66; H, 4.97; N, 8.64.

Found: C, 66.26; H, 5,16; N, 8.64.

Similarly, the remaining benzyl esters listed in A above can beconverted to their respective acids.

EXAMPLE Vllll p-Carbobenzoxybenzoyl chloride is prepared according tothe procedure of H. Zahn and B. Seidel, Makromol. Chem. 19, 71 (1959)and reacted with 5,6-dimethylbenzimidazole according to the generalprocedure of example 1 to give l-(4'-carbobenzoxybenzoyl)-5,6-dimethylbenzimidazole in 55 percent yield; m.p.147-l50 C.

Hydrogenolysis of 1-( 4'-carbobenzoxybenzoyl )-5 ,6-dimethylbenzimidazole according to the procedure of example V-E affordsl-(4-carboxybenzoyl)-5,6-dimethylbenzimidazole in 70 percent yield. m.p.290-308 C.

Anal. Calcd for C H,.,N O C, 69.37; H, 4.80; N, 9.52.

Found: C, 69.40; H, 5.06; N, 9.02.

EXAMPLE 1X The l-aroyl benzimidazoles below can be prepared frompcarbobenzoxybenzoyl chloride and the appropriate benzimidazolesaccording to the procedure of example Vlll.

l-( 4 -carboxybenzoyl ,-dimethoxybenzimidazole I 4'-carboxybenzoyl)-2-methyl-5 ,6-dimethoxybenzimidazole l-(4'-carboxybenzoyl)-2,5,6-trimethylbenzimidazole in example X to give the l-aroylbenzimidazolesin Table III, Column B.

5 TABLE III EXAMPLE X A B A.2-(2-Carbobenzoxyethyl)-5-chlorobenzimidazole b 'tf y ethgll-sl- I b l 22 b m I) 5 Into a l-liter, 3-necked flask, fitted with a stirrer,dropping mm 8 ye y l funnel, immersion thermometer, and refluxcondenser, con- 2-(2-carboXyethyl)-5- taining 250 ml. of benzyl alcohol,is added 22.5 g. 0.10 bmmbemmidm' i, "":i moles) of2-(2'-carboxyethyl)-5-chlorobenzimidazole, prepared according to theprocedure of A. T. James and E. E. 2-(2'-curboxyethyl)-S- Turner, J.Chem. Soc., 1515 1950). To this stirred suspenbmmbemimidam' 'i i i gsion at 10 C., is added dropwise 40 ml. of thionyl chloride. :g: Afterthe addition is complete, the mixture is slowly heated to2-(2'-carboxyethyl)-5- 100 C. and stirred at this temperature for 4hours. The reac- "'e'hylbenzimidamle ffi' 'Q'jfF' r tion mixture iscooled, 300 ml. of ether is added, and the mix- 2 (2, carboxyethy|) 5 ye ture is stored in the refrigerator overnight. The crystals of themelhylbenzimidazolg benzyl ester, i.e., 2-(2'-carbobenzoyethyl)-5- I yvh chlorobenzimidazole are filtered and dissolved in chloroform. 2 (2,cmboxyethy|) 5 mc'hylbenz'm'dazole The chloroform solution is washedsuccessively with a 5 permethymenzimidame cent solution of sodiumcarbonate and water, dried, and y y l evaporated. Recrystallization fromchloroform-ligroin promflhylbenz'm'damlc vides 9.6 g. (31 percent)ofpure product, m.p. l3 ll32 C.

Anal. CalcD for C, H, CIN 02: C, 64.87; H, 4.80; N, 8.90 Found: c,64.88; H, 4.65; EXAMPLE 9 h M l d A solution of 0.10 moles of2-(2'-carboxyethyl)-5-carbox- 'carbbenz9xyet ylysfc orobenzlm' azo e15reacte ybenzimidazole, prepared according to the procedure of A. T. withbenzoyl chloride according to the general procedure of James and TurnerJ Chem. Soc. 1515 (950) in about example I to gwe a 74 Percen} w y '5200 ml. of benzyl alcohol is treated with about 50 ml. ofthiobobenzoxyethyl)fs'chlombenzlm'dazole 78 35 nyl chloride in themanner described in example X-A.

prePaFauon of ]'benZ0yl'2'(2 'carboxyethyn's' The resultant dibenzylester, i.e. 2-(2'-carbobenzoxyethyl)- chlorobenzlmldzole I5-carbobenzoxybenzimidazole, is reacted with benzoyl Hydrogefloiysls ofcarbobenzoxyethyn's' chloride, according to the procedure described inexample I to chlorobenzimidazole according to the procedure of examplegive l benZoyl 2 (zgcarbobenzoxyethyl) 5 carbobenzox V-E affords a 64percent yield of lbenzoyl-2(2-carbox- 40 ybenzimidaz0|e y y -P- 1120460Hydrogenolysis of this latter compound according to the Analcalc'd forC17Hl3ClNzO31 62.12; H, 393; N, procedure of example V-E providesl-benzoyl-2-(2'-carbox- Fol-Ind: 10C, 62-26; H,yethyl)-5-carboxybenzimidazole. 4.39; If], 8.72.l-(4-Chlorobenzoyl)-2-(2'-carboxyethyl)-5-carbox- Simllarly. y y yybenzimidazole and l-(4'-bromobenzoyl-2-(2-carboxyethyl)-chlolobenlimidalole and y S-carboxybenzimidazole can be similarlyprepared by reacting yethyl)- -br0m0benzimid z le r p par a cor g 10 thep-chlorobenzoyl chloride and p-bromobenzoyl chloride, above proceduresusing p-chlorobenzoyl chloride and prespectively, with2-(2-carbobenzoxyethyl)-5-carbobenzoxbromobenzoyl chloride,respectively, instead of benzoyl ybenzimidazole and hydrogenolyzing theresultant products chloride. according to the procedure of example V-E.

EXAMPLE XI EXAMPLE XIII The benzimidazoles in column A of table III,prepared ac- 5 5 A. Preparation of l-aroyl benzotriazoles cording to theprocedure of A. T. James and E. E. Turner, 1. The l-benzoyltriazoles intable IV are prepared by reacting Chem. Soc., 1515 (l950), are reactedwith the appropriate the appropriate benzoyl chlorides andbenzotriazoles accordbenzoyl chlorides in accordance with the proceduredescribed ing to the general procedure of example I.

TABLE IV Elemental analysis Melting Calculated Found point, Yield,l-Aroyl benzotriazole 0 percent C H N C II Nl-(4-carbobenzoxymethoxybenzoyl)-5,6-dl- 130-31 60.38 5.10 10.12 60. 436.08 0.82

meth ylbenzotriazole l-benzoyl-5-chlorobenzotrluzole. 00-101 80 60.683.13 16.31 60.06 2. 00 16.02 LOU-dimethylaminobenzoyl)-5chl0r0benz0triazole -32 20 50.00 4. 35 18.66 50.50 4.27 18.051-(3,4,6-trimethoxybenzoyl)-chlorobenzotriaz e 105-72 30 55.33 4.0612.00 55. ll 3.04 12.41 1-(2',6-dimethoxybenzoyl)-5-chlorobenzotrlazole-81 11 56. 70 3.80 M23 50.73 4. 05 13.3.41-(4-chlorobenzoyl)-5-eh1orobenzotriazole 134-38 62 53.45 2.41 14.3853.70 2.76 14. 1' l-(4-dimethylaminobenzoyl)-5.6(1Irnethylbenzotriazole.107-08 20 00.37 0.10 10.04 00.55 0.01 10.05

EXAMPLE XIV l. The compound 2. The compound CHJO 0 3 OCH

2. The compound